FR2717802A1 - Novel aromatic compounds, process for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Novel n-arylaliphatic-n-alkyl-functionalised amides of formula (I), wherein Am is in particular a substituted piperidyl group. A method for preparing these compounds, and pharmaceutical compositions containing them are also disclosed. The compounds are neurokinin receptor antagonists.

Description

 The present invention relates to novel aromatic compounds, a process for their preparation and pharmaceutical compositions containing it as an active ingredient.

More particularly, the present invention relates to a new class of aromatic compounds for therapeutic use, in pathological phenomena that involve the tachykinin system such as for example without limitation: pain (D. Regoli et al., Life Sciences, 1987, 40, 109-117), allergy and inflammation (JE Morlay et al., Life Sciences, 1987, 41, 527-544), circulatory insufficiency (J. Losay et al., 1977, Substance P, Von Euler, US and Pernow cd., 287293, Raven Press, New York), gastrointestinal disorders (D. Regoli et al., Trcnds
Pharmacol. Sci., 1985, 6, 481-484), respiratory disorders (J. Mizrahi et al.,
Pharmacology, 1982, 25, 39-50).

 In recent years, many research projects have been carried out on tachykinins and their receptors. Tachykinins are distributed both in the central nervous system and in the peripheral nervous system. Tachykinin receptors have been recognized and are classified into three types: NK1, NK2, NK3. The substance P (SP) is the endogenous ligand of the NK1 receptors, the neurokinin A (NKA) that of the NK2 receptors and the neurokinin B (NK, that of the NK3 receptors.

 The NK1, NK2, NK3 receptors have been shown to be present in different species.

 A recent review of CA. Maggi et al. takes stock of tachykinin receptors and their antagonists (J. Autonomic Pharmacol., 1993, 13, 23-93).

 NK1-receptor-specific antagonists include the following non-peptide compounds: CP-96345 (J. Med Chem, 1992, 35, 2591-2600), RP68651 (Proc Natl Acad Sci USA, 1991). 88, 10208-10212), SR 140333 (J. Curr.

Pharmacol., 1993, 250, 403-413).

 For the NK2 receptor, a selective non-peptide antagonist, SR 48968 has been described in detail (Life Sci., 1992, PL101-PL106).

It has now been found that certain aromatic compounds possess valuable pharmacological properties as neurokinin receptor antagonists and are particularly useful for the treatment of any pathological substance.
P and neurokinin dependent.

dans laquelle:
- Am représente:
i- soit un groupe Am1 de formule:

dans laquelle J1 représente: il soit un groupe

dans lequel R2 représente un phényle non substitué ou substitué une ou plusieurs fois par un substituant choisi parmi : un atome d'halogène, un hydroxyle, un alcoxy cn
C1-C4, un alkyle en C1-C4, un trifluorométhyle, lesdits substituants étant identiques ou différents; un pyridyle ; un thiényle ; un pyrimidyle ; un imidazolyle non substitué ou substitué par un alkyle en C1 -C4 ; i2- soit un groupe

dans lequel R2 est tel que défini ci-dessus; i3- soit un groupe

dans lequel:
- R2 est tel que défini ci-dessus;
- x est zéro ou un;
- X1 représente un hydrogène; un hydroxyle ; un alcoxy en C1 -C4; un alkyl-
carbonyloxy dans lequel l'alkyle est en C1-C6 ; un benzoyloxy ; un carboxy ; un
alcoxycarbonyle dans lequel l'alcoxy est en C1-C4 ; un amino ; un groupe
-NR3COR4 ; un cyano ; un groupe -CH2NH2; un groupe -CH2NR3COR4; un
groupe -CH2OH; un groupe -CH2-GAlk dans lequel Alk représente un alkyle en
C1-C4 ; un groupe -CH2-O-COR4;
- ou bien X1 forme avec l'atome de carbone auquel il est lié et avec l'atome de
carbone voisin dans la pipéridine une liaison supplémentaire;
- R3 représente un hydrogène ou un alkyle en C1 -C4;
- R4 représente un alkyle en C1 -C7; un cycloalkyle en C3-C7 non substitué ou
substitué par un ou plusieurs méthyles ; un phényle ; un pyridyle;
i-soit un groupe dans lequel:
- R2 est tel que défini cidessus;
- X2 représente un atome d'oxygène ; un atome de soufre ; un sulfoxyde ; une
sulfone ; un groupe ZR3-; un groupe NCGA1k dans lequel Alk représente
un alkyle en C1-C4 ; un group-N-(CH2)p-NR5R6 ;
- R3 est tel que défini cidessus;
-pest un, deux ou trois;
- R5 et R6 représentent chacun indépendamment un hydrogène ou un alkyle en
C1-C4
- ou bien R5 et R6 ensemble avec l'atome d'azote auquel ils sont liés constituent un
hétérocycle choisi parmi la pyrrolidine, la pipéridine ou la morphotine,
ii- soit un groupe Am2 de formule:

dans laquelle J2 représente:
/
r soit un groupe R2-N\
/
H2- soit un groupe R2-CH2-N\ dans lesquels R2 est tel que défini ci-dessus;
iii- soit un groupe Am3 de formule:

dans laquelle X3, X4, X5 ensemble et avec l'atome d'azote auquel ils sont liés forment un système azabicyclique ou azatricyclique contenant de 5 à 9 atomes de carbone, non substitué ou substitué par un phényle ou un benzyle;
- A- représente un anion;
- Ar représente un phényle non substitué ou substitué une ou plusieurs fois par un
substituant choisi parmi : un atome d'halogène, un hydroxyle, un alcoxy en C1-C4,
un alkyle en C1-C4, un trifluorométhyle, lesdits substituants étant identiques ou
différents ; un thiényle ; un benzothiényle ; un naphtyle ; un indolyle non substitué
ou N-substitué par un alkyle en C1-C4 ou un benzoyle;
- R1 représente un #-(C1-C4)alcoxy(C2-C4)alkylène ; un *(C1-C4
alkylcarbonyloxy(C2-Cq)alkylène ; un o-benzoyloxy(C2-Cq)aIkylène ; un o >
hydroxy(C2-C4)-alkylène; un #-(C1-C4)alkylthio(C2-C4)alkylène ; un o > (C1-
C4)alkylcarbonyl(C2-C4)alkylène ; un #-carboxy(C2-C4)alkylène ; un *(C1-
C4)-alcoxycarbonyl(C2-C4)alkylène ;
- T représente une liaison directe ; un groupe hydroxyméthylène ; un groupe
alcoxyméthylène dans lequel l'alcoxy est en C1-C4 ; un groupe alkylène en C1 -C5;
un vinylène ; un atome d'oxygène ; un groupe -NR7-;
- R7 représente un hydrogène ou un alkyle en C1-C4;
- Z représente:
- un phényle non substitué ou substitué une ou plusieurs fois par un substituant choisi parmi : un atome d'halogène ; un trifluorométhyle ; un cyano ; un hydroxyle ; un nitro ; un amino non substitué ou substitué une ou deux fois par un alkyle en C1 -C4; un benzylamino ; un carboxy ; un alkyle en C1-C10 ; un cycloalkyle en C3-Cg non substitué ou substitué une ou plusieurs fois par un méthyle; un alcoxy en C1-C10 ; un cycloalkyloxy en C3-Cg non substitué ou substitué une ou plusieurs fois par un méthyle ; un mercapto; un alkylthio en C1-C10 ; un alkylcarbonyloxy dans lequel l'allyle est en C1-C6 ; un alkylcarbonylamino dans lequel l'alkyle est en C1-C6; un benzoylamino ; un alcoxycarbonyle dans lequel l'alcoxy est en C1 -C4 ; un cycloalkyloxycarbonyle dans lequel le cycloalkyle est en C3-C7 ; un carbamoyle non substitué ou substitué une ou deux fois par un allyle en C1-C4 ; un uréido non substitué ou substitué une ou deux fois en position 3 par un alkyle en C1-C4 ou un cycloalkyle en C3-C7 ; un (1-pyrrolidino)carbonylamino, lesdits substituants étant identiques ou différents;
- un naphtyle non substitué ou substitué une ou plusieurs fois par un halogène, un trifluorométhyle, un alkyle en C1-C4, un hydroxyle, un alcoxy en C1-C4;
- un pyridyle ; un thiényle ; un indolyle ; un quinoléyle ; un benzothiényle ; un imidazolyle; avec la limitation que R1 ne peut pas représenter un *(Cl-C4)alcoxy (C2-C4)alkylène ou un o-(C1 Cq)alkylcarbonyloxy(C2-Cq)allrylène lorsque Am représente un groupe Am; ainsi que leurs sels éventuels avec des acides minéraux ou organiques ou leurs sels d'ammonium quaternaire éventuels.Thus according to one of its aspects, the present invention relates to compounds of formula:

in which:
- Am represents:
i- is an Am1 group of formula:

in which J1 represents: it is a group

in which R2 represents a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom, a hydroxyl, an alkoxy cn
C1-C4, C1-C4 alkyl, trifluoromethyl, said substituents being the same or different; pyridyl; thienyl; pyrimidyl; unsubstituted or substituted C1-C4 alkyl-substituted imidazolyl; i2- be a group

wherein R2 is as defined above; i3- be a group

in which:
R2 is as defined above;
- x is zero or one;
- X1 represents a hydrogen; a hydroxyl; C1-C4 alkoxy; an alkyl
carbonyloxy wherein the alkyl is C1-C6; a benzoyloxy; a carboxy; a
alkoxycarbonyl wherein the alkoxy is C1-C4; an amino; a group
-NR3COR4; a cyano; a -CH 2 NH 2 group; a group -CH2NR3COR4; a
-CH2OH group; a group -CH2-GAlk in which Alk represents an alkyl in
C1-C4; a group -CH 2 -O-COR 4;
- or else X1 forms with the carbon atom to which it is bonded and with the atom of
adjacent carbon in piperidine an additional bond;
- R3 represents a hydrogen or a C1-C4 alkyl;
- R4 represents a C1-C7 alkyl; unsubstituted C3-C7 cycloalkyl or
substituted with one or more methyls; phenyl; pyridyl;
i-a group in which:
R2 is as defined above;
X 2 represents an oxygen atom; a sulfur atom; a sulfoxide; a
sulfone; a group ZR3-; a group NCGA1k in which Alk represents
C1-C4 alkyl; a group-N- (CH 2) p-NR 5 R 6;
- R3 is as defined above;
-pest one, two or three;
R5 and R6 are each independently hydrogen or alkyl
C1-C4
- or R5 and R6 together with the nitrogen atom to which they are attached constitute a
heterocycle chosen from pyrrolidine, piperidine or morphotine,
ii- is an Am2 group of formula:

in which J2 represents:
/
r is a group R2-N
/
H2- is R2-CH2-N1 in which R2 is as defined above;
iii- is a group Am3 of formula:

wherein X3, X4, X5 together and with the nitrogen atom to which they are attached form an azabicyclic or azatricyclic system containing 5 to 9 carbon atoms, unsubstituted or substituted by phenyl or benzyl;
- A- represents an anion;
Ar represents a phenyl which is unsubstituted or substituted one or more times with one
substituent selected from: a halogen atom, a hydroxyl, a C1-C4 alkoxy,
a C1-C4 alkyl, a trifluoromethyl, said substituents being identical or
different ; thienyl; a benzothienyl; a naphthyl; an unsubstituted indolyl
or N-substituted with C1-C4 alkyl or benzoyl;
- R1 represents a # - (C1-C4) alkoxy (C2-C4) alkylene; a * (C1-C4
alkylcarbonyloxy (C2-C4) alkylene; o-benzoyloxy (C2-C4) alkylene; an o>
hydroxy (C2-C4) -alkylene; a # - (C1-C4) alkylthio (C2-C4) alkylene; an o> (C1-
C4) alkylcarbonyl (C2-C4) alkylene; a # -carboxy (C2-C4) alkylene; a * (C1-
C4) -alkoxycarbonyl (C2-C4) alkylene;
T represents a direct bond; a hydroxymethylene group; a group
alkoxymethylene wherein the alkoxy is C1-C4; a C1-C5 alkylene group;
a vinylene; an oxygen atom; a group -NR7-;
- R7 represents a hydrogen or a C1-C4 alkyl;
Z represents:
a phenyl that is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom; trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino unsubstituted or substituted one or two times by a C1-C4 alkyl; benzylamino; a carboxy; C1-C10 alkyl; C3-C8 cycloalkyl unsubstituted or substituted one or more times with methyl; C1-C10 alkoxy; C3-C8 cycloalkyloxy unsubstituted or substituted one or more times with methyl; a mercapto; C1-C10 alkylthio; an alkylcarbonyloxy in which the allyl is C1-C6; an alkylcarbonylamino wherein the alkyl is C1-C6; a benzoylamino; an alkoxycarbonyl wherein the alkoxy is C1-C4; cycloalkyloxycarbonyl wherein the cycloalkyl is C3-C7; carbamoyl which is unsubstituted or substituted once or twice with a C1-C4 allyl; a ureido which is unsubstituted or substituted once or twice in the 3-position by a C1-C4 alkyl or a C3-C7 cycloalkyl; (1-pyrrolidino) carbonylamino, said substituents being the same or different;
a naphthyl which is unsubstituted or substituted one or more times with a halogen, a trifluoromethyl, a C1-C4 alkyl, a hydroxyl or a C1-C4 alkoxy;
a pyridyl; thienyl; indolyl; quinolyl; a benzothienyl; imidazolyl; with the proviso that R 1 can not represent a (C 1 -C 4) alkoxy (C 2 -C 4) alkylene or o- (C 1 -C 4) alkylcarbonyloxy (C 2 -C 4) allrylene when Am is a group Am; as well as their possible salts with inorganic or organic acids or their possible quaternary ammonium salts.

 When Am represents Am1 or Am2, salts of the compounds of formula (T) can be formed. These salts also include those with inorganic or organic acids which allow a suitable separation or crystallization of the compounds of formula (I), such as picric acid or oxalic acid or an optically active acid, for example a mandelic acid. or camphorsulfonic acid, than those which form pharmaceutically acceptable salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate, 2-naphthalenesulfonate, glycolate, gluconate, citrate, isethionate.

dans laquelle:
- J1 est tel que défini ci-dessus pour (1);
- Q représente un alkyle en C1-C6 ou un benzyle ; ledit substituant étant soit en
position axiale soit en position équatoriale;
- A(9 est un anion.When Am is Aml, the quaternary ammonium salts of the compounds of formula (I) can be formed. The group Am is then represented by the group Amq of formula:

in which:
- J1 is as defined above for (1);
Q is C1-C6 alkyl or benzyl; said substituent being either
axial position in equatorial position;
- A (9 is an anion.

 the compounds of formula (1) according to the invention include both racemic, optically pure isomers, as well as axial and equatorial isomers when in the compound of formula (1), Am represents Am4.

 The anions A are those normally used to salify the quaternary ammonium ions, preferably the chloride, bromide, iodide, hydrogen sulfate, methanesulfonate, paratoluenesulfonate, acetate, benzenesulfonate ions.

 Preferentially, the pharmaceutically acceptable anions are used, for example chloride, methanesulphonate or benzenesulphonate.

 In the present description the alkyl groups or the alkoxy groups are straight or branched; halogen atom is understood to mean a chlorine, bromine, fluorine or iodine atom.

When Z is a phenyl group, that Ci pcut is mono or disubstituted, in particular in position 2,4, but also for example in position 2, 3 or 4, 5 or 3, 4, or 3, 5; it can also be trisubstituted, in particular in position 2, 4, 6 but also for example in 2, 3, 4 or 2, 3, 5 or 2, 4, 5 or 3, 4, 5; tetrasubstituted, for example, 2, 3, 4, 5; or pentasubstituted. In the substituents of the phenyl group, C 1 -C 10 alkyl is, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-pentyl, hexyl or n-hexyl, heptyl or n-heptyl, octyl or n-octyl, nonyl or n-onnyl, decyl or n-decyl; by C3-C8 cycloalkyl optionally substituted by methyl is meant for example cyclopropyl, cyclobutyl, cyclopentyl, 1-, 2- or 3-methylcyclopentyl, cyclohexyl, 1-, 2-, 3- or 4- methylcyclohexyl, cycloheptyl or cyclooctyl; C1-C10 alkoxy means, for example, methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy; by C3-C8cycloalkyloxy optionally substituted with methyl is meant for example a cyclopropyloxy, a cyclobutyloxy, a cyclopentyloxy, a 1-, 2- or 3-methylcyclopentyloxy, a cyclohexyloxy, a 1-, 2-, 3- or 4-methylcydobexyloxy cycloheptyloxy or cyclooctyloxy; C 1 -C 10 alkylthio is, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, secbutylthio, tert-butylthio, pentylthio, hexylthio, heptylthio, octylthio, nonylthio or decylthio; by alkylcarbonyloxy in which the allyl is C 1 -C 6 is meant for example formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, caproyloxy, heptanoyloxy; an alkylcarbonylamino in which the alkyl is C1-C6 is meant for example a formylamino, an acetylamino, a propionylamino, a butyrylamino, an isobutyrylamino, a valerylamino, a caproylamino or a heptanoylamino; by alkoxycarbonyl in which the alkoxy is in
C1-C4 is understood to mean, for example, methoxycarbonyl, ethoxycarbonyl, npropoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl or tert-butoxycarbonyl; by cycloalkyloxycarbonyl in which the cycloalkyl is C3-C7 is meant for example cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl or cycloheptyloxycarbonyl.

 Advantageously, the radical Z represents a phenyl that is unsubstituted or substituted one or more times with a halogen atom, more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl or a C1 -C4 alkyl, a hydroxyl, C1-C4 alkoxy; a naphthyl unsubstituted or substituted one or more times with halogen, trifluoromethyl, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy; pyridyl; thienyl; indolyl; quinolyl; a benzothienyl; an imidazolyl.

dans lequel Rû x et X1 sont tels que définis précdemment. A group of preferred compounds of the invention consists of the compounds of formula (I) in which Ar, R1, T and Z are as defined above and Am is the group of formula:

wherein R x and X 1 are as previously defined.

dans laquelle X1 est tel que défini précédemment ;
- R1 représente un groupe 2-hydroxyéthyle ou un groupe 2-acetoxysthylc ou un
groupe 2-méthoxyéthyle;
- T représente une liaison;
- Z représente un phényle;
- Ar est tel que défini précédemment.Particularly preferred compounds are those of formula (in which both:
Am represents a group of formula:

wherein X1 is as previously defined;
R1 represents a 2-hydroxyethyl group or a 2-acetoxystyl group or a
2-methoxyethyl group;
T represents a bond;
Z represents a phenyl;
Ar is as defined above.

Another group of particularly preferred compounds are those of formula (I) in which both:
Am represents a group of formula:

* soit un groupe

- x is zero or one;
- T represents a methylene;
Z represents a 3-isopropoxyphenyl;
- Ar and R1 are as defined for the compounds of formula (1);
the quaternary ammonium salts which are particularly preferred according to the present invention are those of formula (1) in which:
Am represents a group Am4 in which J1 represents:

* a group

Q is as defined previously and is in axial position;
- T represents a methylene;
Z represents a 3-isopropoxyphenyl group;
- Ar and R1 are as defined for the compounds of formula (1);
- A represents an anion, preferably a pharmaceutically anion
acceptable.

 Another group of preferred compounds of the invention consists of the compounds of formula (f) in which Ar, R 1, T and Z are as defined above and Am is the group Am 3.

représenté par le substituant Am3O+ dans la formule (I) est de préférence le résidu d'un système azabicyclique ou azatricydique choisi parmi: (a) 1 -azoniabicyclo[22.0]hexane (b) 1-azoniabicyclo[3.1 .0]hexane (c) 1-azoniabicyclo[2.2.1]heptane
(d) 1-azoniabicyclo[2.2.2]octane (quinuclidine) (e) 1-azoniabicyclo(3.2. 1]octane (f) 1-azoniabicydo[3.2.2]nonane (g) 1-azoniabicyclo[3.3.1]nonane (h) hexahydro 1H-pyrrolizinium-4 (i) octahydroindolizinium-4 (.j) octahydro 2H-quinolizinium-5 (k) 1-azoniatricyclo[3.3.1.1.3.7]décane (1) 4-phényl-l-azoniabicyclo[2.2.2]octane (phényl-4 quinuclidine).The radical

represented by the substituent Am3O + in formula (I) is preferably the residue of an azabicyclic or azatricylic system selected from: (a) 1-azoniabicyclo [22.0] hexane (b) 1-azoniabicyclo [3.1.0] hexane (c) ) 1-azoniabicyclo [2.2.1] heptane
(d) 1-azoniabicyclo [2.2.2] octane (quinuclidine) (e) 1-azoniabicyclo [3.2.1] octane (f) 1-azoniabicyclo [3.2.2] nonane (g) 1-azoniabicyclo [3.3.1] nonane (h) hexahydro 1H-pyrrolizinium-4 (i) octahydroindolizinium-4 (1) octahydro-2H-quinolizinium-5 (k) 1-azoniatricyclo [3.3.1.1.3.7] decane (1) 4-phenyl-1-azoniabicyclo [2.2.2] octane (4-phenylquinuclidine).

Particularly preferred compounds are those of formula (I) in which both:
Am represents a radical (d) or (I) as defined above for the radical
Am3 +, with A (9 representing an anion, preferentially an anion
pharmaceutically acceptable;
- T represents a methylene;
Z represents a 3-isopropoxyphenyl group;
- Ar and R1 are as defined for the compounds of formula (I).

dans laquelle Ar est tel que défini précédemment, R'1 représente un o (Cl- C4)alcoxy(C2-C4)alkylène, un Fhydroxy(C2-C4)alkylène, un > (C1-
C4)alkylthio(C2-C4)alkylène, un #-(C1-C4)alkylcarbonyl(C2-C4)alkylène, un o- carboxy(C2-C4)alkylène, un #(-(C1-C4)alcoxycarbonyl(C2-C4)alkylène, étant entendu que lorsque R'1 représente un #-hydroaxy(C2-C4)alkylène, l'hydroxyle peut être protégé, et E représente l'hydrogène ou un groupe Oprotecteur tel que par exemple le tétrahydropyran-2-yle,
- soit avec un dérivé fonctionnel d'un acide de formule:
HOCO-T'-Z (n') dans laquelle Z est tel que défini précédemment et T' représente une liaison directe, un groupe hydroxyméthylène, un groupe alcoxyméthylène dans lequel l'alcoxy est en C1-
C4, un groupe aikylène en C1-Cs ou un vinylène, lorsqu'on doit préparer un composé de formule (I) où T est une liaison directe, un groupe hydroxyméthylène, un groupe alcoxyméthylène dans lequel l'alcoxy est en C1 -C4, un groupe aikylène en C1 -C5 ou un vinylène,
- soit avec un chloroformiate de formule:
CICOOZ R dans laquelle Z est tel que défini précédemment, lorsqu'on doit préparer un composé de formule (l)où T est un oxygène,
- soit avec un isocyanate de formule:
O=C=N-Z (V) dans laquelle Z est tel que défini précédemment, lorsqu'on doit préparer un composé de formule (1) où T est un groupe -NR7- dans lequel R7 est un hydrogène,
- soit avec un chlorure de carbamoyle de formule:

According to another of its aspects, the present invention relates to a process for the preparation of the compounds of formula (I) and their salts, characterized in that:
1) treating a compound of formula:

in which Ar is as defined above, R'1 represents an o (Cl-C4) alkoxy (C2-C4) alkylene, a (C2-C4) hydroxyalkylene, a (C1-
C4) alkylthio (C2-C4) alkylene, a # - (C1-C4) alkylcarbonyl (C2-C4) alkylene, an o-carboxy (C2-C4) alkylene, a # (- (C1-C4) alkoxycarbonyl (C2- C4) alkylene, it being understood that when R'1 represents a # -hydroaxy (C2-C4) alkylene, the hydroxyl may be protected, and E represents hydrogen or an Oprotector group such as, for example, tetrahydropyran-2-yl ,
or with a functional derivative of an acid of formula:
HOCO-T'-Z (n ') wherein Z is as defined above and T' represents a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy is C1-
C4, a C1-C6 alkylene group or a vinylene, when a compound of formula (I) where T is a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy is C1-C4, is to be prepared, a C1-C5 alkylene group or a vinylene,
or with a chloroformate of formula:
In which Z is as defined above, when a compound of formula (I) in which T is oxygen is to be prepared,
or with an isocyanate of formula:
Where Z is as defined above, when a compound of formula (1) where T is a group -NR7- in which R7 is hydrogen, is to be prepared,
or with a carbamoyl chloride of formula:

in which Z is as defined above, and R'7 represents a Cn alkylc
C1-C4, when a compound of formula (1) in which T is -NR7 in which R7 is C1-C4alkyl is to be prepared to give a compound of the formula:

dans laquelle E, Ar, T et Z sont tels que définis précédemment et R"1 représente un J (C1-C4)alkylcarbonyloxy(C2-C4)alkylène ou un #-benzoyloxy(C2-C4)alkylène, ou on protège l'hydroxyle;
3) puis on hydrolyse le composé ainsi obtenu à l'étape 1) ou à l'étape 2), pour obtenir l'alcool de formule:

2) optionally when R '1 represents an oe-hydroxy (C2-C4) alkylene, an O-acylation reaction is carried out to obtain a compound of formula:

in which E, Ar, T and Z are as defined above and R "1 represents a C1-C4 alkylcarbonyloxy (C2-C4) alkylene or a # -benzoyloxy (C2-C4) alkylene, or is protected hydroxyl;
3) and then the compound thus obtained is hydrolysed in step 1) or in step 2) to obtain the alcohol of formula:

4) the alcohol (VIII) is treated with methanesulfonyl chloride to obtain the mesylate of formula:

dans laquelle J1 est tel que défini précédemment pour (I), étant entendu que lorsque J1 représente le groupe:

où X1 est un hydroxyle ou un amino, ces groupes peuvent être protégés;
- soit avec une amine secondaire cyclique de formule:

dans laquelle J2 est tel que défini précédemment pour (1),
- soit avec une amine tertiaire cyclique de formule:

dans laquelle X3, X4 et X5 sont tels que définis préodemment pour (I) ; et
6) - soit, lorsqu'on utilise une amine secondaire de formule (X) ou (xI), et après déprotection éventuelle des groupes hydroxyles ou du groupe amino, on transforme éventuellement, le produit ainsi obtenu en un dc ses sels avec un acide minéral ou organique ou un de ses sels d'ammonium quaternaire,
- soit, lorsqu'on utilise une amine tertiaire dc formule (XII) et après déprotectiou
éventuelle du groupe hydroxyle, on isole le produit ainsi obtenu ou bien,
éventuellement on échange l'anion méthanesulfonate du sel quaternaire ainsi
obtenu avec un autre anion, par exemple un anion pharmaccutiquement
acceptable.S) the mesylate is reacted (
or with a cyclic secondary amine of formula:

in which J1 is as defined above for (I), it being understood that when J1 represents the group:

where X 1 is hydroxyl or amino these groups may be protected;
or with a cyclic secondary amine of formula:

wherein J2 is as previously defined for (1),
or with a cyclic tertiary amine of formula:

wherein X3, X4 and X5 are as previously defined for (I); and
6) - or, when a secondary amine of formula (X) or (xI) is used, and after optional deprotection of the hydroxyl groups or of the amino group, the product thus obtained is optionally converted into one of its salts with an acid mineral or organic or a quaternary ammonium salt thereof,
- or, when using a tertiary amine of formula (XII) and after deprotectiou
hydroxyl group, the product thus obtained is isolated or
optionally the methanesulphonate anion of the quaternary salt is exchanged
obtained with another anion, for example a pharmaccuiquement anion
acceptable.

dans laquelle Ar et R1 sont tels que définis précédemment et J représente un groupe J1 ou un groupe J2 tel que définis précédemment, étant entendu que lorsque J1 représente le groupe:

où X1 est un hydroxyle ou un amino, ces groupes peuvent être protégés, et/ou lorsque
R1 représente un groupe -hydroxy(C2-C4)alkylène, l'hydroxyle peut être protégé, avec l'un des composés (E), (il), (V) ou (VI) tels que définis précédemment, et
2') après déprotection éventuelle des groupes hydroxyles ou du groupe amino, on transforme éventuellement le produit obtenu en un de ses sels avec un acide minéral ou organique ou en un de ses sels d'ammonium quatcrnaire. According to a variant of the process, when Am represents Am 1 or Am 2
1 ') a compound of formula

in which Ar and R1 are as defined above and J represents a group J1 or a group J2 as defined above, it being understood that when J1 represents the group:

where X 1 is hydroxyl or amino, these groups may be protected, and / or
R1 represents a-hydroxy (C2-C4) alkylene group, the hydroxyl may be protected with one of the compounds (E), (II), (V) or (VI) as defined above, and
2 ') after optional deprotection of the hydroxyl groups or the amino group, the product obtained is optionally converted into one of its salts with an inorganic or organic acid or a quaternary ammonium salt thereof.

à la condition que R'1 soit différent d'un #-(C1-C4)alcoxy(C2-C4)alkylène, sont nouveaux et font partie de l'invention.The compounds of formula:

provided that R'1 is different from a # - (C1-C4) alkoxy (C2-C4) alkylene, are new and form part of the invention.

à la condition que R1 soit différent d'un {Cl-C4)alcoxy(C2-C4)alkylène ou d'un #-alkylcarbonyloxy(C2-C4)alkylène, sont nouveaux et font partie de l'invention.The compounds of formula:

provided that R 1 is other than a (C 1 -C 4) alkoxy (C 2 -C 4) alkylene or a # -alkylcarbonyloxy (C 2 -C 4) alkylene, are novel and form part of the invention.

à la condition que R1 soit différent d'un o > -(C1-C4)alcoxy(C2-C4)aIkylène ou d'un #-(C1-C4)alkylcarbonyloxy(C2-C4)alkylène, sont nouveaux et font partie de l'invention.The compounds of formula:

with the proviso that R 1 is other than a -> (C 1 -C 4) alkoxy (C 2 -C 4) alkylene or # - (C 1 -C 4) alkylcarbonyloxy (C 2 -C 4) alkylene, are new and form part of the invention.

sont nouveaux et font partie de l'invention.The compounds of formula:

are new and part of the invention.

 O-protecting groups optionally used to obtain a compound of formula (f) in which R 1 represents a (C 2 -C 4) -hydroxy-hydroxy and / or X 1 represents hydroxy are the conventional O-protecting groups well known to humans. such as, for example, tetrahydropyran-2-yl, acetyl or benzoyl.

 The N-protecting groups optionally used to obtain a compound of formula (I) in which X 1 represents an amino are the conventional N-protecting groups well known to those skilled in the art such as, for example, the trityl group, methoxytrityl , ten-butoxycarbonyl or benzyloxycarbonyl.

 In particular, when an O-protecting group is used as an acetyl group or a benzoyl group, the compound of formula (1) obtained represents the final product in which R 1 represents a (C 2 -C 4) -acetoxy alkylene and / or X-1 represents an acetoxy or R1 represents a -Benzoyloxy (C2-C4) alkylene and / or X1 represents a benzoyloxy.

 Depending on whether it is desired to obtain a compound of formula (I) wholly or partially protected, the appropriate protecting groups and / or N-protecting groups are chosen.

 In stage 1) or in stage 1 '), as functional denuded of the acid (III), the acid itself, suitably activated for example by 1,3dicylohexylcarbodiimide or by hexafluorophosphate of benzotriazol-1-yloxytris (dimethylamino) phosphonium (BOP), or one of the functional derivatives which react with the amines, for example an anhydride, a mixed anhydride, the acid chloride, or an activated ester, such as the ester of nitrophenyl.

 When a chloroformate of formula (W) is used, the reaction is carried out in a solvent such as dichloromethane, at a temperature between 0 ° C. and room temperature and in the presence of a base such as triethylamine.

 When an isocyanate of formula (V) is used, the reaction is carried out in an inert solvent such as dichloromethane or benzene overnight at room temperature.

 When a carbamoyl chloride of formula (VI) is used, the reaction is carried out in a solvent such as toluene or 1,2-dichloroethane, at a temperature of between 80 and 1100 ° C. and in the presence of a base such as than triethylamine.

When starting from a compound of formula (II) wherein E is tetrahydropyran-2-yl (top), the process of the present invention can be represented and illustrated by Scheme 1 below:
SCHEME 1

<tb><SEP> R '
<tb><SEP> O <SEP>: <SEP> (11, <SEP> E = 'flIP)
<tb><SEP> o <SEP> Ar
<tb><SEP> 1) <SEP> HOCO-T <SEP> Z <SEP> (III) <SEP> or
<tb><SEP> CICOOZ <SEP> (IV) <SEP> or
<tb><SEP> O = C = N (V) or
<tb><SEP>dCONR'-Z<SEP> (VI)
<tb><SEP> 2) <SEP> When <SEP>R'1<SEP> = <SEP> (shydrozcy (C2-C4) al41ene
<tb><SEP> possibly <SEP> Osrotection <SEP> or <SEP> Oscillation
<tb> R1
<tb> GCH2-CH2tH2 <SEP> lR1 <SEP> TZ <SEP> (VII): <SEP> (VII, <SEP> E <SEP> = <SEP> THP)
<tb><SEP> Ar
<tb><SEP> hydrolysis <SEP> (H <SEP> +)
<tb><SEP> R1
<tb><SEP> HO <H2 <SEP> CH2vf TZ <SEP> (VII <SEP> I)
<tb><SEP> Ar
<tb><SEP> i <SEP> CH3SO2C1
<tb><SEP> R1
<tb><SEP> CH, SO <SEP> ICH-CH2AC <SEP> T <SEP> Z <SEP> (IX)
<tb><SEP> I
<tb><SEP> (X) <SEP> or <SEP> (XI) <SEP> or <SEP> (XII) <SEP> + <SEP> any deprotection <SEP>
<tb><SEP> (I)
<Tb>
The reactions of the compound (II ') with the reagents (III), (IV), (V) or (VI) proceed as described above.

 In the particular case where R '1 represents a (2-hydroxy) (C 2 -C 4) ylene, optionally the hydroxyl is protected, or optionally an O-acylation reaction is carried out according to the usual methods.

 The intermediate (VII ') thus obtained is deprotected by acid hydrolysis to yield the compound (seen), it being understood that when R1 represents a (C2-C4) alkhydroxyalkylene and the hydroxyl is protected, this protecting group is preserved in these operating conditions.

 The mesylate (IN) is then prepared to substitute it with a cyclic secondary amine of formula (X) or (XI) or with a cyclic tertiary amine of formula (XII).

Finally, after any deprotection of the hydroxyl groups or the amino group, the compounds (I) according to the invention are finally obtained.

 When, according to a variant of the process, the compound (Xm) is reacted with one of the compounds (III), (II), (V) or (seen), the product obtained can either represent the final product or own one or more protective groups. In the latter case, the O-protecting groups and / or the N-protecting groups are optionally hydrolysed according to the usual methods.

The products of formula (I) thus obtained are:
either isolated in free base or salt form, according to conventional techniques, when Am represents Aml or Am2,
or, when Am represents Am3, the product thus obtained is isolated or alternatively the methanesulphonate anion of the quaternary salt thus obtained is exchanged with another pharmaceutically acceptable anion.

 When the compound of formula (I) in which Am represents Am 1 or Am 2 is obtained in free base form, the salification is carried out by treatment with the chosen acid in an organic solvent. By treatment of the free base, dissolved for example in an alcohol such as isopropanol, with a solution of the acid selected in the same solvent, the corresponding salt is obtained which is isolated according to conventional techniques.

Thus, for example, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, methanesulphonate, oxalate, maleate, fumarate and naphthalene-2-sulphonate are prepared.

At the end of the reaction, the compounds of formula (I) in which Am represents
Am 1 or Art 2 can be isolated in the form of one of their salts, for example the hydrochloride, or the oxalate; in this case, if it is necessary, the free base can be prepared by neutralizing said salt with a mineral or organic base, such as sodium hydroxide or triethylamine or with an alkaline carbonate or bicarbonate, such as carbonate or sodium bicarbonate or potassium.

The methanesulphonate anion derived from the reaction between the tertiary amine of formula (XII) and the methanesulfonyloxy derivative of formula (I) can be exchanged, in situ or after isolation of the compound of formula (I) in which Am represents a group
Am3 in which A (t is the methanesulphonate ion, by another anion A, according to conventional methods, for example by exchange in solution with a saturated solution of sodium chloride or with a solution of hydrochloric acid when
A represents a chloride anion or by exchange of the anion by elution of the compound (I) on an ion exchange resin, for example Amberlite IRA68 or
A375 Duolite (8).

The quaternary ammonium salts formed with the piperidine nitrogen are prepared by reacting the free bases of the compounds of formula (1) in which Am represents Am 1, for which the other amino functional groups, optionally present, are N-protected by a group N-protector, such as for example tertbutoxycarbonyl, with an excess of alkylating agent of formula:
AQ in which A is as defined above for (I), preferably a chloride or an iodide and Q is as defined above for (I) and the reaction mixture is heated in a solvent, for example dichloromethane, chloroform, acetone or acetonitrile, at a temperature between room temperature and reflux for one to several hours to obtain after treatment according to the usual methods and after possible deprotection, a mixture of axial and equatorial isomers of quaternary ammonium salts .

Preferably, A represents an iodide which can be exchanged by another anion or by a pharmacologically acceptable anion, for example a chloride, by elution of the compound (I) on an ion exchange resin, for example Amberlite IRA68 t) or
Duolite A375 (!).

 The isomers are separated according to the usual methods, for example by chromatography or by recrystallization.

 The resolution of the racemic mixtures (I) makes it possible to isolate the enantiomers.

dans laquelle E et Ar sont tels que définis ci-dessus, par réduction puis substitution de l'amine obtenue.The starting compounds of formula (II) are prepared from nitriles of formula

in which E and Ar are as defined above, by reduction and then substitution of the amine obtained.

The reduction of nitriles of formula (XW) is carried out by hydrogenation in an alkanol such as ethanol, in the presence of a catalyst such as, for example, nickel.
Raney 8 and, after isolation according to conventional methods, the primary amine of formula

(II, R'= #-hydroxy(C2-C4)alkylène) est isolée selon les méthodes habituelles.To prepare a compound of formula (11) in which R '1 represents an o-hydoxy (C 2 -C 4) alkylene group, the amine (XV) is treated with ethyloxalyl chloride, ethyl hemimalonate or by ethyl hemisuccinate, for example, and the corresponding N-acyl derivatives are obtained. The carbonyl groups are then reduced according to the usual methods, such as the action of a reducing agent such as, for example, a metal hydride, such as lithium aluminum hydride or a boron hydride, such as dimethylsulphide. borane. The reduction is carried out in a solvent such as tetrahydrofuran or toluene at a temperature between room temperature and 60.degree. The amine thus obtained of formula:

(II, R '= # -hydroxy (C2-C4) alkylene) is isolated by the usual methods.

 In particular, the reaction of glycolic acid with amine (XV) in the presence of BOP and triethylamine can be used to obtain the corresponding N-acyl derivative which, after reduction of the carbonyl group, makes it possible to obtain a compound of formula (11) wherein R'1 represents a 2-hydroxyethyl group.

 When the w-hydroxy (C2-C4) alkylene group constitutes the R1 group of the final compound of formula (I), it is necessary to protect the hydroxyl function. This protection step can be carried out conventionally either at the level of the compound (II) or at the level of the compound (VII), by using an Oprotector group which will not be hydrolysed during the deprotection of the group E (step 3) .

 To prepare a compound of formula (II) wherein R'1 is - (C1-C4) alkoxy (C2-C4) alkylene, the amine (XV) is reacted with a (C1-C4) alkoxy acid (C2-C4) alkanoic, in the presence of BOP and a base such as triethylamine, and then the carbonyl group of the N-acylated derivative obtained intermediately is reduced.

To prepare a compound of formula (11) in which R '1 represents a # (C2-C4) alkoxycarbonyl alkylene, the amine (XV) is reacted with a C1-C4 (C2-C4) -halkylenecarboxylate alkyl such as, for example, ethyl 3-bromopropionate, ethyl 4-bromobutyrate or methyl 5-bromovalerate
The hydrolysis of compounds of formula (II) in which R '1 represents a o- (C1-C4) alkoxycaibonyl (C2-C4) alkylene leads, according to conventional methods, compounds of formula (11) in which R'1 represents an oe-carboxy (C2-C4) alkylene.

 To prepare a compound of formula (11) in which R '1 represents a (C2-C4) alkylthloalkylene, the amine (XV) is reacted with a # -halogeno (C2-C4) alkylenethioalkyl (C1-C4) such for example 2-chloro-1-methylthioethane.

The nitriles of formula (XW) are prepared from commercial nitriles or known nitriles of formula:
Ar-CH2-CN (XVI) by alkylation with a compound of formula: E-OCH2-CH2-G (XVII) wherein E is as defined above and G is a halogen atom, for example bromine.

qui est ensuite mis en réaction, en présence d'hydrure alcalin avec le dérivé acétonitrile (XVI) pour préparer l'intermédiaire,

Preferably, the synthesis of nitriles of formula (XIV) in which E is a tetrahydropyran-2-yl group is carried out from a tetrahydropyranyloxy derivative obtained by reaction between an alkanol of formula Br (CH 2) 2 -OH and 3,4 -dihydro-2H-pyran to yield the compound:

which is then reacted in the presence of alkaline hydride with the acetonitrile derivative (XVI) to prepare the intermediate,

The starting compounds of formula (Xm) are prepared from nitriles of formula:

 in which J and Ar are as defined above, by reduction and then substitution of the amine obtained.

The reduction of the nitriles (XVIII) is carried out according to the process described above for the preparation of the compounds of formula (II). The primary amine of formula

 The substitution of the primary amine (XIX) by the R 1 group is carried out using the same methods as those described above for the preparation of the compounds of formula (II). In the particular case where R 1 is a (C 2 -C 4) -hydroxy-alkylene, optionally after protection of the secondary amine obtained, an acylation is carried out, then after deprotection of the amine, a compound of formula tXE) is obtained in which R 1 is a # - (C1-C4) alkylcarbonyloxy (C2-C4) alkylene or an o> - benzoyloxy (C2-C4) alkylene.

un dérivé nitrile de formule:
Ar-CH2-CN (XVI) en présence d'amidure de sodium dans un solvant tel que le toluène à des températures comprises entre 30 et 80-C. The nitriles of formula (XVIII) are synthesized according to known methods by reacting chlorinated derivatives of formula:

a nitrile derivative of formula:
Ar-CH2-CN (XVI) in the presence of sodium amide in a solvent such as toluene at temperatures between 30 and 80 ° C.

lui-même préparé à partir de l'amine de formule:

sur laquelle on fait réagir, l'oxyde d'éthylène étant entendu que lorsque J1 représente le groupe:

où X1 est un hydroxyle ou un amino, ces groupes peuvent être protégés.The chlorinated derivative (XX) is prepared by the action of a chlorinating reagent such as, for example, thionyl chloride on the hydroxyl derivative of formula:

itself prepared from the amine of formula:

on which is reacted, ethylene oxide being understood that when J1 represents the group:

where X 1 is hydroxyl or amino these groups may be protected.

 The piperidines of formula (X) are known or prepared by known methods, such as those described in EP-A-0428434, EP-A-0474561, EP-A0515240 and EP-A-559438.

dans lequel R2 est un pyrid2yle, x est zéro et X1 est l'hydroxyle, on fait réagir la 2-bromopyridine sur la N-benzyl-4-pipéridone dans un solvant en présence de butyllithium pour préparer la N-benzyl-4-hydrxy-4tpyrid-2-ylcF pipéridine.For example, when in a piperidine of formula (X), J 1 represents a group

wherein R2 is pyridyl, x is zero and X1 is hydroxyl, 2-bromopyridine is reacted with N-benzyl-4-piperidone in a solvent in the presence of butyllithium to prepare N-benzyl-4-hydroxy 4-pyrid-2-ylf piperidine.

Compounds of formula (X) in which X 1 represents a hydroxyl and which carry a protecting group on the nitrogen of piperidine, can undergo a reaction of
Ritter by action of acetonitrile to prepare the compounds of formula (X) wherein X1 is an acetamido.

 By hydrolysis in an acid medium, the compounds of formula (X) in which X 1 is amino are then prepared. Optionally, the substitution of the amino group by a R '3 = C 1 -C 4 alkyl group can be carried out. By action of a functional derivative of an acid R4COOH, compounds of formula (X) in which X1 is the group R4CONR3 are prepared.

 Piperazines of formula (XI) are known or prepaid by known methods, such as those described in EP-A-0474561.

The amines of formula (XII) are those described in the literature, for example those mentioned below:
(a ') 1-azabicyclo [2.2.0] hexane prepared according to CA. Grob et al., Helv. Chim. Acta,
1964; (47), 8, 2145-55.

(b ') 1-azabicyclo [3.1.0] hexane prepared according to AL Logothetis, J. Am. Chem. Soc., 1965, (87), 4, 749-754.

(c ') 1-azabicyclo [2.2.1] heptane prepared according to Gassman et al., J. Am. Chem. Soc., 1968, (90), 5, 1355-6.

(d ') 1-azabicyclo [2.2.2] octane or quinuclidine.

(e ') 1-azabicyclo [3.2.1] octane prepared according to B. Thill et al., J. Org. Chem., 1968, (33), 12, 476-80.

 (P) 1-azabicyclo [3.2.2] nonane prepared according to C. Ruggles et al., J. Am.

Soc., 1988, (110), 17, 5692-8.

(g ') 1-azabicyclo [3.3.1] nonane prepared according to S. Miyano et al., J. Chem. Soc.,
Perkin Trans 1, 1988.5, 1057-63.

(i') octahydro indolizine-4 préparée selon J. Chastanet et al., J. Org. Chem., 1985, (50), 16, 2910-14.

(h ') hexahydro 1H-pyrrolizine-4 prepared according to P. Edwards et al., Tetrahedron
Letters, 1984, (25), 9, 939-42.

(i ') octahydro indolizine-4 prepared according to J. Chastanet et al., J. Org. Chem., 1985, (50), 16, 2910-14.

(.i ') octahydro 2H-quinolizine-5 prepared according to P. Edwards et al., Tetrahedron
Letters, 1984, (25), 9, 939-42.

 (k ') 1-azatricyclo [3.3.1.1.3.7] decane, or 1-azadamantane, prepared according to Y.

(1') 4-phényl-1-azabicydo[2.2.2joctane, ou phényl-4 quinuclidine, préparé selon T. Perrine, J. Org. Chem., 1957, 22, 1484-1489.

Bubnov et al., J. Organomet. Chem., 1991, 412 (1-2), 1-8.

(1 ') 4-phenyl-1-azabicyclo [2.2.2] octane, or 4-phenylquinuclidine, prepared according to T. Perrine, J. Org. Chem., 1957, 22, 1484-1489.

 The resolution of the racemic mixtures (') makes it possible to isolate the enantiomers (1 *).

susceptibles de donner des sels avec des acides optiquement actifs.However, it is preferable to perform the resolution of the racemic on the intermediate aminoalcohols of formula:

capable of giving salts with optically active acids.

 The aminoalcohols (XV, E = H) are obtained from the compounds (XV *, E = THP) after deprotection by hydrolysis in an acid medium.

 The enantiomers (XV *, E = H) are then separated by conventional methods such as those described in EP-A-0428434 and EP-AX474561.

 The preparation of optically pure compounds of formula (Vffl) is illustrated in Scheme 2 below where "*" means that the carbon atom thus marked is of (+) or (-) configuration determined.

SCHEME 2

I;) CHMiLCYNH <SEP> (XV) :( E <SEP> T
<tb><SEP> Ar
<tb><SEP> Ar
<tb><SEP> HO {: <SEP> 1FCHz <SEP> NH2 <SEP> (XV) <SEP>: (E = H)
<tb><SEP> Ar
<tb><SEP> separation <SEP> of <SEP> enantiomers
<tb><SEP> *
<tb><SEP> HO {H24I2wl2 <SEP> NH2 <SEP> (XV *) <SEP>: <SEP> (E <SEP> = <SEP> H)
<tb><SEP> I
<tb><SEP> Ar
<tb><SEP> *
<tb> 3L.
<Tb>

est alors soumis à l'action du chlorure de méthanesulfonyle pour conduire au dérivé (IX*) optiquement pur de formule:

<SEP> 0 <SEP> (XV *) <SEP>: (E <SEP> TIP)
<tb><SEP> l <SEP> R '
<tb> R ', <SEP>(It'
<tb><SEP><SEP> Ar <SEP> H
<tb><SEP> 1) <SEP> (II <SEP> or (N) or <SEP> 03 <SEP> or <SEP> (vI) <SEP>,
<tb><SEP> 2) <SEP> Oscillation <SEP> eventual <SEP> when
<tb><SEP>R'1<SEP> = <SEP> (shydroxy (C2 {: 4) alkylene
<tb><SEP> R1
<tb><SEP> CZCICT-Z <SEP> (VII '*)
<tb><SEP> O <SEP> Ar
<tb><SEP> H +
<tb><SEP> (VIII *)
<Tb>
The compound thus obtained of formula:

is then subjected to the action of methanesulfonyl chloride to yield the optically pure derivative (IX *) of formula:

 The products of formula (I) in which T represents a hydroxymethylene group, C1-C4 alkoxymethylene, have two centers of asymmetry.

In this case, the diastereoisomers and the pure isomers can be prepared by reacting the optically pure amino alcohol (in *, E = H) and HOCOT-Ar acid either optically pure or racemic, wherein r represents a hydroxymethylene group or a C1-C4 alkoxymethylene group.

The reaction of the mesylate (six *) with a compound of formula (X) or a compound of formula (XI) or a compound of formula (XII), according to the conditions described for obtaining (I) above, allows the preparation of the compounds (1 *), after possible deprotection, and possible transformation of the products thus obtained into one of their salts
The compounds of formula (I) above also include those in which one or more hydrogen or carbon atoms have been replaced by their radioactive isotope, for example tritium or carbon-14. Such labeled compounds are useful in research, metabolism or pharmacokinetic work in biochemical assays as receptor ligands.

 The compounds according to the invention have been the subject of biochemical tests.

 Some compounds (I) and (1 *) and their salts showed antagonistic properties of Substance P binding in tests performed on rat cortex membranes and IM9 lymphoblastic cells, according to MA. Cascieri et al., J. Biol. Chem., 1983, 258 5158-5164 and D.D. Paya et al., J. Immunol., 1984, 133.3260-3265.

 Certain compounds and their salts have shown NKA antagonistic properties in rat duodenum membrane assays, according to L Bergstom et al., J. Immunol., 1987, 2, 764-771.

 Compounds that have been shown to be potent antagonists of Substance P inhibit its binding to its receptor with an inhibition constant (Ki) of between 10-8 M and 10-10 M in the various biochemical tests performed. .

Compounds that have proven to be potent antagonists of Neurokinin
A inhibit the binding thereof to its receptor with an inhibition constant (Ki) of between 10-8 M and 10-10 M in the various biochemical tests carried out.

 The compounds of the present invention are especially active ingredients of pharmaceutical compositions, the toxicity of which is compatible with their use as medicaments.

 The compounds of formula (I) above may be used at daily doses of 0.01 to 100 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg / kg. in humans, the dose may preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5 to 1000 mg per day depending on the age of the subject to be treated or the type of treatment: prophylactic or curative .

 For their use as medicaments, the compounds of formula (I) are generally administered in dosage units. Said dosage units are preferably formulated in pharmaceutical compositions in which the active ingredient is mixed with a pharmaceutical excipient.

 Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I).

 In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredients can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers. , animals and humans. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral forms of administration, subcutaneous forms of administration, intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.

 When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The sucrose tablets or other suitable materials may be coated or treated so that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.

 A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

 A preparation in syrup or elixir form may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptic, as well as a flavoring agent and a suitable colorant.

 The water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or color correcting agents. taste.

 For rectal administration, suppositories are used which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.

 For parenteral, intranasal or intraoculal administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersing agents and / or pharmacologically compatible wetting agents, for example propylene glycol or butylene glycol, are used.

 For administration by inhalation, an aerosol containing, for example, sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoromethane or any other biologically compatible propellant gas is used.

 The active ingredient may also be formulated in the form of microcapsules, optionally with one or more supports or additives.

 In each dosage unit, the active ingredient of formula (I) is present in the amounts adapted to the daily doses envisaged. In general, each dosage unit is suitably adjusted according to the dosage and the type of administration envisaged, for example tablets, capsules and the like, sachets, ampoules, syrups and the like, drops so that such a dosage unit contains 0.5 to 1000 mg of active ingredient, preferably 2.5 to 250 mg to be administered one to four times daily.

According to another of its aspects, the present invention relates to the use of the products of formula (I) for the preparation of medicaments intended to treat physiological disorders associated with an excess of tachykinins, in particular of Substance
P and all neurokinin-dependent pathologies of the respiratory, gastrointestinal, urinary, immune, cardiovascular and central nervous system as well as pain and migraine.

For example and without limitation:
- Acute and chronic pain related for example to migraine, pain of
cancerous and anginal, chronic inflammatory processes such as
osteoarthritis and rheumatoid arthritis,
- inflammations such as obstructive chronic respiratory diseases,
Asthma, allergies, rhinitis, hypersensitivity eg pollen and
mites, rheumatoid arthritis, osteoarthritis, psoriasis, ulcerative colitis,
Crohn's disease, inflammation of the intestines (irritable colon), prostatitis, bladder
neurological, cystitis, urethritis, nephritis,
- diseases of the immune system related to suppression or stimulation
functions of the immune cells for example rheumatoid arthritis, psoriasis,
Crohn's disease, diabetes, lupus,
- diseases of the central nervous system such as anxiety, depression,
psychosis, schizophrenia, mania, dementia, epilepsy,
Parkinson's, Alzheimer's, drug addiction, Down syndrome
and Huntington's chorea and neurodegenerative diseases,
- diseases of the gastrointestinal system such as nausea, irritable colon,
gastric and duodenal ulcers, diarrhea, hypersecretions,
- diseases of the cardiovascular system such as hypertension,
vascular migraine, edema, thrombosis, angina pectoris and
vascular spasms.

 The present invention also includes a method for treating said conditions at the doses indicated above.

In the Preparations and in the examples the following abbreviations are used:
EtOH: ethanol
MeOH: methanol
Ether: diethyl ether
Ether iso: diisopropyl ether
DMF: dimethylformamide
AcOEt: ethyl acetate
DCM: dichloromethane
THF: tetrahydrofuran
NaOH: soda
iPr: isopropyl
TA: room temperature
F: melting point
NMR: nuclear magnetic resonance.

s: singlet
se: expanded singlet d: doublet
td: split triplet
seven: sevenuplet
m: massive
PREPARATIONS.

Preparation 1
3-isopropoxyphenylacetic acid.

 a) Ethyl ester of 3-hydroxyphenylacetic acid.

 A mixture of 55 g of 3-hydroxyphenylacetic acid in 400 ml of absolute EtOH and a few drops of concentrated sulfuric acid is refluxed overnight. The reaction mixture is evaporated under vacuum, the residue is taken up in ether, washed with water, with saturated sodium hydrogencarbonate solution, dried over magnesium sulphate and the solvent is evaporated off under vacuum. 58 g of the expected product are obtained in the form of an oil which is used as it is in the next step.

 b) Ethyl ester of 3-isopropoxyphenylacetic acid.

 A mixture of 58 g of the compound obtained in the preceding step, 88 g of potassium carbonate and 108 g of 2-iodopropam in 300 ml of DMF is heated at 80 ° -100 ° C. for 8 hours. The reaction mixture is evaporated under vacuum, the residue is taken up in AcOEt, washed with a 10% solution of potassium carbonate, dried over magnesium sulphate and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting with DCM. 61 g of the expected product are obtained in the form of an oil, which is used as it is in the next step.

 c) 3-isopropoxyphenylacetic acid.

A mixture of 31 g of the compound obtained in the preceding step, 20 g of NaOH in 400 ml of EtOH is refluxed for 2 hours. The reaction mixture is evaporated under vacuum, the residue is taken up in water, acidified by addition of concentrated hydrochloric acid to pH = 1, extracted with ether, washed with water, dried over magnesium sulphate and evaporated. under vacuum the solvent. 27 g of the expected product are obtained, mp 33-35 ° C.
Preparation 2
2- (3,4-Difluorophenyl) -4- (tetrahydropyran-2-yloxy) butylamine.

 a) 2d3,4-difluorophenyl) -4-tetrahydropyran-2-yloxy) butanenitrile.

 To a solution of 2.5 g of 3,4-difluorophenylacetonitrile in 250 ml of THF, 6.53 g of 60% sodium hydride in oil are added in portions and the mixture is stirred for 3 hours at RT. . After cooling to -20 ° C., a solution of 34.1 g of 1-bromo-2- (tetrahydropyran-2-yloxy) ethane in 70 ml of MFI is added dropwise and the mixture is left stirring for 18 hours. the temperature at TA. The reaction mixture is evaporated under vacuum, the residue is taken up in ether, washed with water, with a pH = 4 buffer solution, with water, with saturated sodium chloride solution and dried over sodium sulphate. evaporate under vacuum. The residue is chromatographed on silica eluting with toluene. 15 g of the expected product is obtained which is used as such in the next step.

 b) 2d3,4-difluorophenyl) -4-tetrahydropyran-2-yloxy) butylamine.

 A mixture of 15 g of the compound obtained in the preceding step, Raney nickel qD (10% of the amount of starting nitrile) in 200 ml of absolute EtOH and 30 ml of hydrogen is hydrogenated at RT at atmospheric pressure. concentrated ammonia. The catalyst is filtered through Celite Q and the filtrate is evaporated under vacuum. The residue is taken up in ether, washed with water, dried over sodium sulfate and evaporated under vacuum. 14 g of the expected product is obtained, which is used as such in EXAMPLE 4, step A.

EXAMPLE 1
N- [4d4-Benzylpiprid-1-yl2,4-dichlorophenyl) butyl] -N- (2-hydroxyethyl) -3-isopropoxyphe-nyl) acetamide hydrochloride, hemihydrate.

A) N- [4- (4-Benzylpiperid-1-yl) -2- (3,4-dichlorophenyl) butyl] glycolamide.

 To a solution of 14.3 g of 4 <4-benzylpiperid-1-yl 2- (3,4-dichlorophenyl) butylamine dichlorohydrate (prepared in EP-A-428434), 2.52 g of glycolic acid, 9 g of triethylamine in 150 ml of DCM, 13.26 g of BOP are added and the mixture is stirred for 1 hour at RT. The reaction mixture is evaporated under vacuum, the residue is extracted with AcOEt, washed with water, with saturated sodium chloride solution, dried over sodium sulfate and the solvent evaporated under vacuum. 13.5 g of the expected product is obtained which is used as it is in the next step.

B) N- [4- (4-Benzylpiperid-1-yl) -2- (3,4-dichlorophenyl) butyl] tetrahydropyran-2-
yloxy-acetamide.

A solution of 14 g of the compound obtained in the preceding step in 100 ml of DCM is acidified to pH = 1 by addition of a saturated solution of hydrochloric acid in ether. Then a solution of 2.8 g of 3,4-dihydro-2H-pyran in 20 ml of
DCM and stirred for 1 hour at RT. The reaction mixture is concentrated by half, washed with a 10% solution of NaOH, washed with water, dried over sodium sulfate and the solvent evaporated under vacuum. The residue is chromatographed on silica eluting with a DCM / MeOH (100/2, v / v) mixture. 6 g of the expected product are obtained which is used as it is in the next step.

C) N- [2- (tetrahydropyran-2-yloxy) ethyl] -4-benzylpiperid-1-ylF2d3,4-dichloro-phenyl) butylamine.

 A suspension of 1.3 g of aluminum lithium hydride in 50 ml of MFI is heated to 6 ° C. and a solution of 6 g of the compound obtained in the previous step in 50 ml of THF. The mixture is heated for 3 hours at reflux and after cooling, the reaction mixture is hydrolyzed by adding 1 ml of water, then 1 ml of 3N NaOH and 3 ml of water. The inorganic salts are filtered off and the filtrate is evaporated under vacuum.

4.5 g of the expected product is obtained which is used as it is in the next step.

D) N- [4- (4-Benzylpiperid-1-yl) 2,4-dichlorophenylbutyl] -N- [2-tetrahydropyran-2-yloxy) ethyl] - (3-isopropoxyphenyl) acetamide.

 To a mixture of 4.5 g of the compound obtained in the preceding step, 1 g of triethylamine, 1.94 g of 3-isopropoxyphenylacetic acid in 100 ml of DCM, 4.42 g of BOP are added. Then left stirring for 1 hour at RT and evaporated under vacuum.

The residue is taken up in AcOEt, washed with water, with saturated sodium chloride solution, dried over sodium sulphate and evaporated under vacuum. The residue is chromatographed on silica, eluting with a DCM / MeOH (100 / 2.5, v / v) mixture. 3.2 g of the expected product are obtained.

E) N- (4- (4-Benzylpiperid-1-yl) -2- (3,4-dichlorophenyl) butyl] hydrochloride
N- (2-hydroxyethyl) - (3-isopropoxyphenyl) acetamide, hemihydrate.

A solution of 3.2 g of the compound obtained in the preceding step in 50 ml of MeOH is acidified to pH = 1 by addition of a saturated solution of hydrochloric acid in ether. The mixture is stirred for 1 hour at RT and evaporated under vacuum. The residue is taken up in water, neutralized by addition of a 10% solution of NaOH, extracted with AcOEt, washed with water, with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. under vacuum. The residue is chromatographed on silica eluting with the mixture
DCM / MeOH (100/3, v / v). The product obtained is taken up in DCM, acidified to pH = 1 by adding a saturated solution of hydrochloric acid in ether and evaporated under vacuum. 2.5 g of the expected product are obtained after crystallization from a DCM / pentane mixture.

 NMR Spectrum at 200 MHz in DMSO.

1,3ppm: d: 6H
1.4 ppm: m: 7H 2.5 to 3.8ppm: m: 17H
4.6 ppm: seven: 1 H 4.7 to 5.05 ppm: td: 1H
6.5 to 7.9: m: 12 H 10.4ppm: se: 1H
EXAMPLE 2 N- [4- (4-Acetamido-4-phenylpiperid-1-yl) -2- (3,4-dichlorophenyl) butyl] -N- (2-methoxyethyl) benzamide hydrochloride, dihydrate.

A) N- [2- (3,4-dichlorophenyl) -4-tetrahydropyran-2-
yloxy) butyl] methoxyacetamide.

 A mixture of 8.6 g of 23,4-dichlorophenyl (tetrahydropyran-2-yloxy) butylamine (described in EP-A-0474561), 2.46 g of methoxyacetic acid, 5.5 g of triethylamine in 50 ml of DCM, 14.5 g of BOP are added and the mixture is left stirring for 1 hour. After evaporation of the reaction mixture under vacuum, the residue is taken up in AcOEt, washed with water, dried over sodium sulfate and the solvent evaporated under vacuum. The residue is chromatographed on silica, eluting with a DCM / MeOH mixture (100/1, v / v). 7.5 g of the expected product is obtained which is used as such in the next step.

B) Nd2-methoxyethylF2- (3,4-dichlorophenyl) tetrahydropyran-2-ylozcyk
butylamine.

 A suspension of 1.5 g of lithium aluminum hydride in 30 ml of flIF is refluxed and a solution of 7.5 g of the compound obtained in the preceding step in 40 ml of THF is added dropwise. . The mixture is left stirring for 3 hours and then, after cooling, the reaction mixture is hydrolyzed by adding 1 ml of water. The inorganic salts are filtered off and the filtrate is evaporated under vacuum. The residue is chromatographed on silica eluting with a DCM / MeOH mixture (100/1.5 v / v). 4.1 g of the expected product is obtained, which is used as it is in the next step.

C) N- [2- (3,4-dichlorophenyl) -4-tetrahydropyran-2-yloxy) butyl] -N (2-methoxyethyl) benzamide.

To a solution of 2 g of the compound obtained in the preceding step, 1.7 g of triethylamine in 50 ml of DCM, 0.745 g of benzoyl chloride are added and the mixture is left stirring for 1 hour at RT. It is evaporated under vacuum, the residue is taken up in AcOEt, washed with water, dried over sodium sulphate and the solvent evaporated under vacuum. The residue is chromatographed on silica H, eluting with the gradient of the mixture
DCM / MeOH from (100 / 0.5; v / v) to (100/1; v / v). 2.2 g of the expected product is obtained which is used as it is in the next step.

D) N- [2- (3,4-dichlorophenyl) -4-hydroxybutyl] -N2-metboxyethyl) bermamide.

 A solution of 2.2 g of the compound obtained in the step proeeded in 50 ml of MeOH is acidified to pH = 1 by addition of a saturated solution of hydrochloric acid in ether and the mixture is left stirring for 1 hour at RT. It is evaporated under vacuum, the residue is taken up in AcOEt, washed with water, dried over sodium sulphate and the solvent evaporated under vacuum. 1.6 g of the expected product is obtained which is used as such in the next step.

E) N- [2- (3,4-dichlorophenyl) -4-methanesulfonyloxybub] -N {2-methoxyethylF)
benzamide.

 To a solution of 1.6 g of the compound obtained in the preceding step, 0.5 g of triethylamine in 50 ml of DCM is added 0.555 g of methanesulfonyl chloride and stirred for 30 minutes at RT. It is evaporated under vacuum, the residue is taken up in AcOEt, washed with water, dried over sodium sulphate and the solvent evaporated under vacuum. 1 g of the expected product is obtained which is used as it is in the next step.

F) N-14- (4-acetamido-4-phenylpiperid-1-ylt) -2,4-dichlorohydrochloride
phenyl) butyl] -N- (2-methoxyethyl) benzamide, dihydrate.

 A mixture of 1.9 g of the compound obtained in the preceding step, 1.7 g of 4-acitamido-4-phenylpip-Cndint paratoluenesulphonate and 2.8 g of potassium carbonate in 20 ml of sodium hydroxide were refluxed for 5 hours. acetonitrile and 20 ml of DMF. After cooling, the reaction mixture is poured into water, extracted with AcOEt, washed with water, with saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica eluting with a DCM / MeOH (100/3 v / v) mixture. The product obtained is taken up in DCM, acidified to pH = 1 by adding a saturated solution of hydrochloric acid in ether and evaporated under vacuum. 1.4 g of the expected product are obtained after crystallization from a DCM / ether mixture, mp = 139-142 ° C.

EXAMPLE 3
N- [4- (4-acetamide-4-phenylpiperid-1-yl) -2,4-dichlorophenyl) butyl] -N- (2-acetoxyethyl) benzamide hydrochloride, hemihydrate.

A) N- [3,4-dichlorophenyl) -4- (tetrahydropyran-2-) ethyl ester
yloxy) butyl] oxamic.

 A mixture of 19 g of 2- (3,4-dichlorophenyl) -4- (tetrahydropyran-2-yloxy) butylamine, 7 g of triethylamine in 100 ml of DCM is cooled to 0 ° C., and then 8 parts are added dropwise. 2 g of ethyloxalyl chloride and left stirring for 30 minutes, allowing the temperature to rise to RT. After evaporation under vacuum, the residue is taken up in ether, washed with water, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica, eluting with a DCM / MeOH mixture (100/1, v / v). 16 g of the expected product are obtained which is used as such in the next step.

B) N- (2-hydroxyethyl 2- (3,4-dichlorophenyl) -4-tetrahydropyran-2-
yloxy) butylamine.

A suspension of 1.7 g of aluminum hydride and lithium in 60 ml of 111F is heated to 60 ° C. and a solution of 16 g of the compound obtained in the previous step in 40 ml is added dropwise. ml of THF. The mixture is stirred for 4 hours and then, after cooling, the reaction mixture is hydrolyzed by adding 2 ml of water and then 2 ml of 3N NaOH and 6 ml of water. The inorganic salts are filtered off and the filtrate is evaporated under vacuum. The residue is chromatographed on silica eluting with the mixture
DCM / MeOH (100/5, v / v). 7.5 g of the expected product is obtained which is used as it is in the next step.

C) N- [2d3,4-dichlorophenyl 4 tetrahydropyran-2-yloxy) butyl] -Nd 2
hydroxyethyl) benzamide.

 A mixture of 2.5 g of the compound obtained in the preceding step, 0.843 g of benzoic acid and 1.4 g of triethylamine in 50 ml of DCM is cooled to 0 ° C. and 3.7 g of BOP are added. The mixture is left stirring for 1 hour and evaporated under vacuum. The residue is taken up in ether, washed with water, with a pH = 4 buffer solution, with water, then dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica H, eluting with a DCM / MeOH mixture (100/1.5 v / v). 1.2 g of the expected product is obtained which is used as it is in the next step.

D) N- (2-acetoxyethyl N- [23,4-dichloropentyl-4-hydroxybutyl] benzamide.

 To a solution of 1.2 g of the compound obtained in the previous step, 0.3 g of triethylamine in 30 ml of DCM, 0.255 g of acetyl chloride are added and the mixture is stirred for 30 minutes at RT. It is evaporated under vacuum, the residue is taken up in AcOEt, washed with water, dried over sodium sulphate and evaporated under vacuum. The residue is taken up in 20 ml of MeOH, 0.06 g of pyridinium paratoluenesulphonate is added, the mixture is stirred overnight at RT and then refluxed for 30 minutes. It is evaporated under vacuum, the residue is taken up in AcOEt, washed with water, dried over sodium sulphate and evaporated under vacuum. 0.7 g of the expected product is obtained which is used as it is in the next step.

E) N- (2-acetoxyethyl) N- [2d3,4-dichlorophenyl 4-methanesulfonyloxybutyl]
benzamide.

 To a solution of 0.7 g of the compound obtained in the preceding step, 0.180 g of triethylamine in 30 ml of DCM, is added 0.206 g of methanesulfonyl chloride and left stirring for 30 minutes at RT. It is evaporated under vacuum, the residue is taken up in AcOEt, washed with water, with saturated sodium hydrogen carbonate solution, with water, dried over sodium sulphate and evaporated under vacuum. 0.72 g of the expected product is obtained which is used as it is in the next step.

F) N- [4- (4-acetamido-4-phenylpiperid-1-yl) -2- (3,4-A) hydrochloride)
dichlorophenyl-butyl] -N (2-acetoxyethyl) benzamide, hemihydrate.

 A mixture of 0.72 g of the compound obtained in the preceding step and 0.76 g of 4-acetamide-4-phenylpiperidine in 2 ml of DMF is heated at 80 ° C. for 3 hours.

After cooling, the reaction mixture is poured into water, the precipitate formed is filtered and washed with water. The solid is taken up in AcOEt, washed with water, dried over sodium sulphate and evaporated under vacuum. The residue is chromatographed on silica H, eluting with the gradient of the DCM / MeOH mixture (from 100/1.5 v / v) to (10/5 v / v). The product obtained is taken up in DCM, acidified to pH = 1 by adding a saturated solution of hydrochloric acid in ether and evaporated under vacuum. 0.4 g of the expected product is obtained after crystallization from a DCM / ether mixture, mp = 136 ° -138 ° C.

EXAMPLE 4
N- [4q 4 -acetamido-4-phenylpiperid-1-yl 2,4-dichloro-phenyl) butyl] -N- (2-hydroxyethyl) benzamide hydrochloride, sesquihydrate.

 A mixture of 0.2 g of the compound obtained in EXAMPLE 3 and 0.02 g of lithium hydroxide monohydrate in 10 ml of MeOH is stirred at RT for 1 hour.

It is evaporated under vacuum, the residue is taken up in DCM, washed with water, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica H, eluting with a DCM / MeOH mixture (100/5 v / v) and then (100/10 v / v). The product obtained is taken up in DCM, acidified to pH = 1 by adding a saturated solution of hydrochloric acid in ether and evaporated under vacuum. 0.07 g of the expected product is obtained, mp = 177-186 ° C.

EXAMPLES
N- [4H-4-acetamido-4-phenylpiperid-1-yl] -2,4-difluoro (phenyl) butyl] -N (2-hydroxyethyl) benzamide hydrochloride.

A) Ethyl ester of N- [2 {3,4-difluorophenyl 4 {tetrahydropyran-2-
yloxy) -butyl] oxamic.

A mixture of 14 g of the compound obtained in the preparation is cooled to 0 ° C. (2.5.94 g of triethylamine in 100 ml of DCM) and 6.69 g of ethyl oxalyl chloride are added. The mixture is left stirring for 30 minutes while allowing the temperature to rise to RT and then evaporated under vacuum. The residue is taken up in ether, washed with water, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica eluting with the mixture
DCM / MeOH (100/1; v / v). 16.5 g of the expected product are obtained which is used as it is in the next step.

B) N- (2-hydroxyethyl) -2- (3,4-difluorophenyl) -4-tetrahydropyran-2-yloxy)
butylamine.

 A suspension of 6.3 g of lithium aluminum hydride in 180 ml of MFI is heated to reflux and a solution of 16.5 g of the compound obtained in the previous step in 100 ml is added dropwise. ml of THF. The reaction mixture is left stirring for 18 hours under stirring and after cooling, the reaction mixture is hydrolyzed by adding 6 ml of water and then 6 ml of 4N NaOH and 18 ml of water. The inorganic salts are filtered through celite and the filtrate is evaporated under vacuum. The residue is taken up with DCM, dried over sodium sulfate and the solvent evaporated under vacuum. The residue is chromatographed on silica eluting with a DCM / MeOH mixture (95/5, v / v). 5.5 g of the expected product is obtained which is used as it is in the next step.

C) N- (2-benzoyloxyethyl) -N- [2- (3,4-difluorophenyl) -4- (tetrahydropyran-2-)
yloxy) butyl] -benzamide.

 A mixture of 3.2 g of the compound obtained in the preceding step, 2.56 g of triethylamine in 50 ml of DCM is cooled to 0 ° C. and a solution of 2.73 g of benzoyl chloride in 50 ml of benzoyl chloride is added dropwise. ml of DCM. It is left stirring for 1 hour, allowing the temperature to rise to RT and evaporated under vacuum. The residue is taken up in AcOEt, washed with water, with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on silica, eluting with a DCM / MeOH mixture (100/1, v / v). We obtain S g of the expected product which is used as such in the next step.

D) N {2-benzoyloncyethyl N- [2,4-difluorophenyl 4-hydroxybutyl] benzamide.

To a solution of 5 g of the compound obtained in the previous step in 60 ml of
MeOH, 0.230 g of pyridinium paratoluenesulphonate and heated for 30 minutes at reflux. It is evaporated under vacuum, the residue is taken up in AcOEt, washed with water, dried over sodium sulphate and evaporated under vacuum. 4 g of the expected product is obtained which is used as it is in the next step.

E) N- (2-benzoyloxyethyl) -N- (2- (3,4-difluorophenyl) -4-
méthanesulfonyloxybutyl] -benzamide.

 To a mixture of 4 g of the compound obtained in the previous step, 1.16 g of triethylamine in 40 ml of DCM, a solution of 1.11 g of methanesulfonyl chloride in 40 ml of DCM is added. The mixture is stirred for 30 minutes at RT and evaporated under vacuum. The residue is taken up in AcOEt, washed with water, with saturated sodium chloride solution, dried over sodium sulphate and evaporated under vacuum. 4 g of the expected product is obtained which is used as it is in the next step.

F) N- [4- (4-acetamido-4-phenylpiper-1-yl) -2- (3,4-difluorophinyl) butyl] -N-
(2-benzoyloxyethyl) benaamide.

A mixture of 2.2 g of the compound obtained in the preceding step, 1.77 g of 4-acetamido-phenylpiperidine paratoluenesulphonate and 2.29 g of potassium carbonate in 15 ml of ethyl acetate are heated at 80 ° C. for 4 hours. acetonitrile and 2 ml of
DMF. After cooling, the reaction mixture is poured into ice water, extracted with AcOEt, washed with water, with saturated sodium chloride solution and evaporated under vacuum. The residue is chromatographed on silica H, eluting with the mixture
DCM / MeOH (100/2, v / v). 1.7 g of the expected product is obtained which is used as it is in the next step.

G) N- [4- (4-acetamido-4-phenylpiperid-1-yl) -2,4-difluorohydrochloride
phenyl) butyl] -N- (2-hydroxyethyl) benzamide.

To a solution of 1 g of the compound obtained in the previous step in 10 ml of
MeOH, 0.067 g of NaOH is added and the mixture is stirred for 1 hour 30 minutes at RT.
It is evaporated under vacuum, the residue is taken up in DCM, washed with water, with saturated sodium chloride solution, dried over sodium sulphate and evaporated under vacuum. The residue is chromatographed on silica H, eluting with a DCM / MeOH mixture (95/5, v / v). The residue is taken up in DCM, acidified to pH = 1 by adding a saturated solution of hydrochloric acid in ether and evaporated under vacuum. 0.52 g of the expected product is obtained after crystallization from a pentane / ether mixture, mp 184 ° -186 ° C.

EXAMPLE 6
N- [44-Acetamido-4-phenylpiperid-1-yl-2,3,4-difluorophenyl) butyl] -N- (2-benzoyloxyethyl) benzamide hydrochloride.

To a solution of 0.7 g of the compound obtained in EXAMPLE 5, step F in
DCM is added until pH = 1, a saturated solution of hydrochloric acid in ether and evaporated in vacuo. 0.24 g of the expected product is obtained after crystallization from pentane / ether, mp = 148-150 ° C.

Claims (16)

1. Compound of formula:

 in which: - Am represents: i- is a group Am 1 of formula:

 in which J1 represents:  it is a group R2CH = in which R2 represents a phenyl which is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom, a hydroxyl, a C1-C4 alkoxy, a C1-C4 alkyl, a trifluoromethyl, said substituents being the same or different; pyridyl; thienyl; pyrimidyl; unsubstituted or substituted C1-C4 alkyl-substituted imidazolyl; i2-be a group

 wherein R2 is as defined cideusus; i3- be a group

 wherein: R2 is as defined above; - x is zero or one; - X1 represents a hydrogen; a hydroxyl; C1-C4 alkoxy; an alkylcarbonyloxy wherein the allyl is C1-C6; a benzoyloxy; a carboxy; an alkoxycarbonyl wherein the alkoxy is C1-C4; an amino; a group -NR3COR4; a cyano; a -CH 2 NH 2 group; a group -CH2NR3COR4; a  -CH2OH group; a group -CH2-O-Alk in which Alk represents an alkyl  C1-C4; a group -CH 2 -O-COR 4;  - or else X1 forms with the carbon atom to which it is bonded and with the atom of  adjacent carbon in piperidine an additional bond;  - R3 represents a hydrogen or a C1-C4 alkyl;  - R4 represents a C1-C7 alkyl; unsubstituted C3-C7 cycloalkyl or  substituted with one or more methyls; phenyl; pyridyl;  i4- is a group R2-X2-CH-  |  in which: R2 is as defined above; X2 represents an oxygen atom; a sulfur atom; a sulfoxide; a  sulfone; an N- group; a group -NCO-Alk in which Alk represents  |  C1-C4 alkyl; ; a group-N- (CH 2) p-NR 5 R 6;  |  - R3 is as defined above;  -pest one, two or three;  R5 and R6 each independently represent a hydrogen or an alkyl in  C1-C4  - or R5 and R6 together with the nitrogen atom to which they are attached  a heterocycle selected from pyrrolidine, piperidine or morpholine;  ii- is an Am2 group of formula:

 in which J2 represents:  /  ii1-be a group R2-N  or either R2 = {wherein R 2 is as defined above; iii- is a group Am3 of formula:

 quaternary ammonium compounds.  as well as its possible salts with mineral or organic acids or its salts  Am represents a group Am3;  (C2-C4) alkylene or a (o- (C1-C4) alkylcarbonyloxy (C2-C4) alkylene when  with the limitation that R1 can not represent a w- (C1-C4) alkoxy  a pyridyl; thienyl; indolyl; quinolyl; a benzothienyl; imidazolyl;  a naphthyl which is unsubstituted or substituted one or more times with a halogen, a trifluoromethyl, a C1-C4 allyl, a hydroxyl or a C1-C4 alkoxy;  a phenyl that is unsubstituted or substituted one or more times with a substituent chosen from: a halogen atom; trifluoromethyl; a cyano; a hydroxyl; a nitro; an amino unsubstituted or substituted one or two times by a C1-C4 alkyl; benzylamino; a carboxy; C1-C10 alkyl; C3-C8 cycloalkyl unsubstituted or substituted one or more times with methyl; C1-C10 alkoxy; C3-C8 cycloalkyloxy unsubstituted or substituted one or more times with methyl; a mercapto; C1-C10 alkylthio; an alkylcarbonyloxy wherein the alkyl is C1-C6; an alkylcarbonylamino wherein the alkyl is C1-C6; a benzoylamino; an alkoxycarbonyl wherein the alkoxy is C1-C4; cycloalkyloxycarbonyl wherein the cycloalkyl is C3-C7; carbamoyl which is unsubstituted or substituted once or twice with a C1-C4 allyl; a ureido which is unsubstituted or substituted once or twice in the 3-position by a C 1 -C 4 alkyl or a C 3 -C 7 cycloalkyl; (1-pyrrolidino) carbonylamino, said substituents being the same or different;  Z represents:  - R7 represents a hydrogen or a C1-C4 alkyl;  C1-Cs; a vinylene; an oxygen atom; a group -NR7-;  alkoxymethylene wherein the alkoxy is C1-C4; an alkylene group in  T represents a direct bond; a hydroxymethylene group; a group  (C1-C4) -alkoxycarbonyl (C2-C4) alkylene;  (C1-C4) alkylcarbonyl (C2-C4) alkylene; ecarboxy (C2-C4) alkylene; a #-  hydroxy (C2-C4) -alkylene; a # - (C1-C4) alkylthio (C2-C4) alkylene; an o-  alkylcarbonyloxy (C 2 -C 4) alkylene; o-benzoyloxy (C2-C4) alkylene; a w-  - R1 represents a # - (C1-C4) alkoxy (C2-C4) alkylene; a (C1-C4  unsubstituted or N-substituted with C 1 -C 4 alkyl or benzyl;  identical or different; thienyl; a benzothienyl; a naphthyl; an indolyl  C1-C4, a C1-C4 alkyl, a trifluoromethyl, said substituents being  substituent chosen from: a halogen atom, a hydroxyl, an alkoxy  Ar represents a phenyl which is unsubstituted or substituted one or more times with one  - A represents an anion;  carbon, unsubstituted or substituted by phenyl or benzyl;  form an azabicyclic or azatricyclic system containing from 5 to 9 carbon atoms  in which X3, X4, X5 together and with the nitrogen atom to which they are bound 2. Compound according to claim 1, in which Am represents the group of formula:

 0 is an anion.  axial position in equatorial position;  Q represents a C1-C6 alkyl or benzyl; said substituent being either  ~ J1 is as defined above for (1) in claim 1;  in which: 3. Compound according to claim 1 of formula (1) in which Am is the group of formula:

 quaternary.  its salts with mineral or organic acids or its ammonium salts  wherein R2, x and X1 are as defined for (1) in claim 1 and 4. Compounds according to one of claims 1 or 3 of formula:

 its quaternary ammonium salts.  2-methoxyethyl group and its salts with mineral or organic acids or  and R1 represents a 2-hydroxyethylc group or a 2-acetoxyethyl group or a  wherein X1 and Ar are as defined in claim 1 5. Compound according to one of claims 1 or 3 of formula:

 inorganic or organic acids or its quaternary ammonium salts.  Ar, R 1 and x are as defined in claim 1 and its salts with  in which: 6. Quaternary ammonium salt of a compound according to one of claims 1 or 2  of formula:

 and Q is in the axial position.  wherein x, Ar, R 1, Q, A are as defined in claims 1 and 2 7. Compound according to claim 1 characterized in that Am3 is the residue of a  azabicyclic or azatricyclic system chosen from:  (a) 1-azoniabicyclo [2.2.0] hexane (b) 1-azoniabicyclo [3.1.0] hexane  (c) 1-azoniabicyclo [2.2.1] heptane (d) 1-azoniabicyclo [2.2.2] octane  (e) 1-azoniabicyclot 3.2.1] octane  (f) 1-azoniabicyclo [3.2.2] nonane (g) 1-azoniabicyclo [3.3.1] nonane  (h) hexahydro 1H-pyrrolizinium-4  (i) octahydroindolizinium-4  (j) octahydro 2H-quinolizinium-5  (k) 1-azoniatricyclo [3.3.1.1.3.7] decane  (1) 4-phenyl-1-azoniabicyclo [2.2.2] octane. 8. Compound according to claim 7 of formula chosen from:

 in which A, Ar, R 1 are as defined in claim 1. 9. Compound according to one of claims 1 to 8 in the form of a salt  pharmaceutically acceptable. Process for the preparation of a compound according to Claim 1 and its salts  possible, characterized in that:  1) treating a compound of formula:

 in which Ar is as defined above, R'1 represents a (C1-C4) alkoxy (C2-C4) alkylene, a-hydroxy (C2-C4) alkylene, a * (C1- C4) alkylthio (C2-C4) alkylene, a # - (C1-C4) alkylcarbonyl (C2-C4) alkylene, a -carboxy (C2-C4) alkylene, a # (- (C1-C4) alkoxycarbonyl (C2-C4) alkylene, it being understood that when R '1 represents a (C2-C4) alkhydroxyalkylene, the hydroxyl may be protected, and E represents hydrogen or an O-protecting group such as, for example, tetrahydropyran-2-yl, or with a functional derivative of an acid of formula: HOCO-TZ (here) in which Z is as defined above and T represents a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the aicoxy is in C1- C4, a C1-C6 alkylene group or a vinylene, when a compound of formula (') where T is a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy is C1 is to be prepared. C4, a C1-C6 alkylene group or a vinylene,  or with a chloroformate of formula: ## STR3 ## in which Z is as defined above, when a compound of formula (I) in which T is an oxygen is to be prepared;  or with an isocyanate of formula:  O = C = N-Z (V) in which Z is as defined above, when a compound of formula (I) in which T is a group -NR7- in which R7 is hydrogen, is to be prepared,  or with a carbamoyl chloride of formula:

 in which Z is as defined above, and R '7 represents an alkyl in C1-C4, when a compound of formula (where T is a group) NR7- wherein R7 is C1-C4 alkyl, to obtain a compound of formula:

 2) optionally when R '1 represents a hydroxy (C2-C4) alkylene, an O-acylation reaction is carried out to obtain a compound of formula:

  in which E, Ar, T and Z are as defined above and R "1 represents a # - (C1-C4) alkylcarbonyloxy (C2-C4) alkylene or a # -benzoyloxy (C2- C4) alkylene, where the hydroxyl is protected; 3) and then the compound thus obtained is hydrolysed in step 1) or in step 2) to obtain the alcohol of formula:

 4) the alcohol (Vin) is treated with methanesulfonyl chloride to obtain the mesylate of formula:

 5) the mesylate (IX) is reacted  or with a cyclic secondary amine of formula:

 wherein J1 is as defined in claim 1 for (1), with the proviso that when J1 is the group:

 where X 1 is hydroxyl or amino these groups may be protected;  or with a cyclic secondary amine of formula:

  in which J 2 is as defined in claim 1 for (I), or with a cyclic tertiary amine of formula:

 acceptable.  obtained with another anion, for example a pharmaceutically  optionally the methanesulphonate anion of the quaternary salt is exchanged  hydroxyl group, the product thus obtained is isolated or  - or, when using a tertiary amine of formula (XII) and after deprotection  mineral or organic or a quaternary ammonium salt thereof,  optionally converts the product thus obtained into one of its salts with an acid  possible deprotection of the hydroxyl groups or the amino group,  6) - or, when using a secondary amine of formula (x) or (cl), and after  wherein X3, X4 and X5 are as previously defined for (I); and Process for the preparation of a compound according to claim 1 wherein Am  represents Am1 or Am2, characterized in that:  1 ') a compound of formula

 wherein Ar and R1 are as defined in claim 1 and J represents a group J1 or a group J2 as defined in claim 1, it being understood that when J represents the group:

 where X 1 is hydroxyl or amino, these groups may be protected, and / or when R 1 is hydroxy (C 2 -C 4) alkylene, the hydroxyl may be protected with one of the compounds (m), ( II), (V) or (VI) as defined in claim 10, and  2 ') after possible deprotection of the hydroxyl groups or the amino group,  optionally converts the product obtained into one of its salts with an acid  mineral or organic or in one of its quaternary ammonium salts. 12. Compound of formula:

 R'1 is different from a - (C1-C4) alkoxy (C2-C4) alkylene.  in which Ar, R'1 and E are as defined in claim 10, provided that 13. Compound of formula:

 provided that R 1 is other than a (C 1 -C 4) alkoxy (C 2 -C 4) alkylene or a C 1 -C 4 alkoxycarbonyloxy (C 2 -C 4) alkylene.  wherein Ar, R 1, T and Z are as defined in claim 1, at 14. Compound of formula:

 R 1 is other than an o- (C 1 -C 4) alkoxy (C 2 -C 4) alkylene or a (C 1 -C 4) alkyloxycarbonyloxy (C 2 -C 4) alkylene.  wherein Ar, R1, T and Z are as defined in claim 1 with the proviso that 15. Compound of formula:

 the invention.  and Ar and R1 are defined in claim 1 are new and are part of  in which J represents a group J1 or J2 as defined in claim 1 16. Pharmaceutical composition containing as active ingredient a compound according to  any of claims 1 to 8.